The PI proposes that the anterior optic nerve is specifically susceptible to microcirculatory compromise, causing or contributing to the development of various optic nerve disorders, including glaucomatous optic neuropathy. While recognizing the crucial role of intraocular pressure (10P) in many glaucoma patients, the PI puts forward the notion that glaucoma is more appropriately viewed as an optic neuropathy caused by a variety of factors including, but not limited to, increased 10P. Previously, the PI has detailed the microvascular anatomy (methylmethacrylate corrosion casting) of the anterior optic nerve of non-primate mammals, non-human primates and humans. This technique was extended to evaluate the vasomotor response of a variety of agents on the microvascular beds of the eye. To more fully assess the optic nerve and its microvasculature, microsphere optic nerve blood flow and optic nerve topographic analysis has been performed. By exploiting a potent vasoconstrictor peptide (endothelin-1) and a long-term delivery system, an animal model of chronic, low-grade optic nerve ischemia has been developed. With constant infusion of endothelin-1 to the perineural, retrobulbar region of the rabbit, the anterior optic nerve vasculature demonstrates dose-dependent focal vasoconstriction of the supply arterioles, significant reduction in optic nerve blood flow, and significant increase in the optic disk cup volume. Preliminary application of the model in primates has demonstrated similar findings. By employing this model, the effects of prolonged ischemia of the anterior optic nerve will be examined. This model will allow histological (including axonal counts and apoptotic labeling), functional and morphological comparison to optic neuropathies resulting form other stressors, such as elevated 10P. The model will also allow the assessment of the combined effects of optic nerve ischemia and elevated 10P. Finally, possible pharmacologic blockers of decreased optic nerve blood flow and ischemia can be evaluated.